研究者詳細 - 中田　圭

論文 - 中田　圭

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Isolated Right Ventricular Apical Hypoplasia: A Case Report with 18 Years of Follow Up

Takashi Oya, Kakuya Kitagawa, Takanori Kokawa, Hiroshi Nakajima, Shiro Nakamori, Yoshito Ogihara, Kei Nakata, Masaki Ishida, Yasutaka Ichikawa, Hajime Sakuma

Cardiovascular Imaging Asia 2021年

DOI

Serial cardiac magnetic resonance imaging in wet beriberi.

Hiroaki Murakami, Naoki Fujimoto, Keishi Moriwaki, Kei Nakata, Masaki Ishida, Ryuji Okamoto, Masaaki Ito, Kaoru Dohi

Journal of cardiology cases 22 ( 3 ) 100 - 102 2020年09月 [国内誌]

A 69-year-old woman with previous pancreaticoduodenectomy was admitted for evaluation of chest discomfort on effort and leg edema for a few months. Oral flosemide before admission for 1 week failed to relieve her symptoms. Her blood pressure was 105/51 mmHg and heart rate was 76 beats/min. Chest X-ray revealed an enlarged heart and mild pulmonary congestion. Echocardiography demonstrated normal left ventricular ejection fraction and diastolic dysfunction with no left ventricular hypertrophy. Cardiac catheterization showed normal coronary arteries, high cardiac index, and elevated intracardial pressures. Myocardial biopsy from the right ventricular septum revealed nearly normal findings. Cardiac magnetic resonance imaging (CMRI) showed both ventricles enlarged and increased global extracellular volume fraction (ECV) of 37%, but normal native T1 and T2 values. As she had pancreaticoduodenectomy, beriberi was suspected. Vitamin B1 significantly increased urine output and lowered intracardiac pressures and cardiac index. After 3 months of vitamin B1, CMRI exhibited that the right ventricle had decreased in size and the global ECV value had been lowered. Our case highlights that chronic beriberi may be associated with little myocardial damage. The increased ECV suggests that the diffuse expansion of extracellular space unrelated to myocardial edema might have been reversed by vitamin B1treatment. Morphological changes in the ventricles and myocardial damage by wet beriberi can be demonstrated by CMRI. .

DOI PubMed

Reply to the comment of Hirota et al. on "Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes".

Tatsuya Sato, Hiroto Oshima, Kei Nakata, Yukishige Kimura, Toshiyuki Yano, Masato Furuhashi, Masaya Tannno, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation 11 ( 1 ) 256 - 256 2020年01月 [国内誌]

DOI PubMed

mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation.

Koki Abe, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tatsuya Sato, Hidemichi Kouzu, Kei Nakata, Wataru Ohwada, Yukishige Kimura, Hirohito Sugawara, Satoru Shibata, Yusuke Igaki, Shoya Ino, Tetsuji Miura

Biochimica et biophysica acta. Molecular basis of disease 1865 ( 12 ) 165552 - 165552 2019年12月 [国際誌]

Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4 ± 1.3% to 46.1 ± 2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/β, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.

DOI PubMed

Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.

Yukishige Kimura, Atsushi Kuno, Masaya Tanno, Tatsuya Sato, Kouhei Ohno, Satoru Shibata, Kei Nakata, Hirohito Sugawara, Koki Abe, Yusuke Igaki, Toshiyuki Yano, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation 10 ( 4 ) 933 - 946 2019年07月 [国内誌]

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium-glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. MATERIALS AND METHODS: Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. RESULTS: Canagliflozin reduced blood glucose levels in OLETF, and blood β-hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels in the kidney by 3.2- and 1.6-fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll-like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre-MI fasting suppressed MI-induced renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood β-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with β-hydroxybutyrate attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. CONCLUSIONS: The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI-induced cardiorenal syndrome, possibly by β-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.

DOI PubMed

Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes.

Tatsuya Sato, Hiroto Oshima, Kei Nakata, Yukishige Kimura, Toshiyuki Yano, Masato Furuhashi, Masaya Tanno, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation 10 ( 3 ) 846 - 850 2019年05月 [国内誌]

The present study evaluated the accuracy of interstitial glucose measurements by flash glucose monitoring (FGM) and continuous glucose monitoring (CGM). Five diabetes patients simultaneously underwent FGM (FreeStyle Libre Pro) and CGM (iPro™2), and their glucose levels were compared with venous blood and capillary blood glucose levels. The range of daily venous blood glucose levels (30 measurements) was 70-245 mg/dL, with a median of 138 mg/dL. There were good correlations of glucose levels measured by FGM (r2 = 0.90, mean absolute relative difference 8.2 ± 5.6%), CGM (r2 = 0.86, mean absolute relative difference 9.2 ± 9.1%) and capillary blood (r2 = 0.87, mean absolute relative difference 7.2 ± 7.2%) with venous blood glucose levels. The accuracy of FGM measurements was also shown against CGM, with 99.9% of the FGM values (1,279 measurements) being within the Parkes error grid zones A and B. The results suggest that the accuracy of FGM is similar to that of CGM, and that FGM is a useful tool for determining daily glucose profile.

DOI PubMed

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats.

Hiroto Oshima, Takayuki Miki, Atsushi Kuno, Masashi Mizuno, Tatsuya Sato, Masaya Tanno, Toshiyuki Yano, Kei Nakata, Yukishige Kimura, Koki Abe, Wataru Ohwada, Tetsuji Miura

The Journal of pharmacology and experimental therapeutics 368 ( 3 ) 524 - 534 2019年03月 [国際誌]

The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial β-hydroxybutyrate (βOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of βOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

DOI PubMed

Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts.

Masashi Mizuno, Atsushi Kuno, Toshiyuki Yano, Takayuki Miki, Hiroto Oshima, Tatsuya Sato, Kei Nakata, Yukishige Kimura, Masaya Tanno, Tetsuji Miura

Physiological reports 6 ( 12 ) e13741 2018年06月 [国際誌]

To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho-Ser637-Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1-Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes-induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.

DOI PubMed

Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes.

Shingo Muratsubaki, Atsushi Kuno, Masaya Tanno, Takayuki Miki, Toshiyuki Yano, Hirohito Sugawara, Satoru Shibata, Koki Abe, Satoko Ishikawa, Kouhei Ohno, Yukishige Kimura, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Masashi Mizuno, Tetsuji Miura

Scientific reports 7 ( 1 ) 5311 - 5311 2017年07月 [国際誌]

Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

DOI PubMed

Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways.

Makoto Ogasawara, Toshiyuki Yano, Masaya Tanno, Koki Abe, Satoko Ishikawa, Takayuki Miki, Atsushi Kuno, Toshiyuki Tobisawa, Shingo Muratsubaki, Kouhei Ohno, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Tetsuji Miura

Journal of molecular and cellular cardiology 108 203 - 213 2017年07月 [国際誌]

BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-α (TNF) and z-VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6±4.3% to 60.6±2.7%, and the LDH release was suppressed by necrostatin-1 (29.4±4.0%), a RIP1 inhibitor, and by siRNA-mediated knockdown of RIP3 (27.7±2.0%), confirming RIP1-RIP3-dependent necroptosis. TNF/zVAD-induced necroptosis was not attenuated by mPTP inhibitors or GSK-3β inhibitors. TNF/zVAD increased LC3-II level, but the change was not further enhanced by bafilomycin A1. The increase of LC3-II by TNF/zVAD was associated with suppression of both autophagic flux and LC3-LAMP1 co-localization. TNF/zVAD did not modify phosphorylation of Akt, p70s6K, AMPK, ULK1 or VASP but significantly increased RIP1-p62 binding and conversely reduced p62-LC3 binding. Rapamycin inhibited RIP1-p62 and RIP1-RIP3 interactions induced by TNF/zVAD and partly restored autophagic flux and suppressed LDH release in TNF/zVAD-treated cells. The effect of rapamycin on LDH release was reduced by knockdown of Atg5 expression. Knockdown of p62 by siRNA augmented LDH release by TNF/zVAD. CONCLUSION: Suppression of autophagic flux contributes to RIP1-RIP3 interaction and necroptosis of cardiomyocytes, and sequestration of p62 from its interaction with LC3-II by p62-RIP1 interaction possibly underlies the suppressed autophagy. The mPTP is unlikely to play a major role in execution of necroptosis in cardiomyocytes.

DOI PubMed

Distinct impacts of sleep-disordered breathing on glycemic variability in patients with and without diabetes mellitus.

Kei Nakata, Takayuki Miki, Masaya Tanno, Hirofumi Ohnishi, Toshiyuki Yano, Atsuko Muranaka, Tatsuya Sato, Hiroto Oshima, Yuki Tatekoshi, Masashi Mizuno, Koki Abe, Tetsuji Miura

PloS one 12 ( 12 ) e0188689 2017年 [国際誌]

BACKGROUND: Sleep-disordered breathing (SDB) is highly prevalent in patients with diabetes mellitus (DM) and heart failure (HF) and contributes to poor cardiovascular outcomes. Enlarged glycemic variability (GV) is a risk factor of cardiac events independently of average blood glucose level, but the influence of SDB on GV is uncertain. In this study, we examined whether the impact of SDB on GV is modified by the presence of DM with or without HF. METHODS AND RESULTS: Two hundred three patients (67.5±14.1 [SD] years old, 132 males) who were admitted to our institute for examination or treatment of DM and/or HF underwent continuous glucose monitoring and polysomnography. Both HbA1c (8.0±2.0 vs. 5.7±0.4%) and mean amplitude of glycemic excursion (MAGE, median: 95.5 vs. 63.5 mg/dl) were significantly higher in a DM group (n = 100) than in a non-DM group (n = 103), but apnea-hypopnea index (AHI: 29.0±22.7 vs. 29.3±21.5) was similar in the two groups. AHI was correlated with log MAGE in the non-DM group but not in the DM group, and multivariate regression analysis revealed that AHI was an independent variable for log MAGE in the non-DM group but not in the DM group. We then divided the non-DM patients into two subgroups according to BNP level (100 pg/ml). AHI was positively correlated with log MAGE (r = 0.74, p<0.001) in the non-DM low-BNP subgroup, but such a correlation was not found in the non-DM high-BNP subgroup. Continuous positive airway pressure (CPAP) reduced MAGE from 75.3 to 53.0 mg/dl in the non-DM group but did not reduce MAGE in the DM group. CONCLUSION: Severity of SDB was associated with higher GV, but DM as well as HF diminished the contribution of SDB to GV. Treatment with CPAP was effective for reduction of GV only in patients without DM.

DOI PubMed

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